Delta14-pregnen-3,21-diol-20-one-21 acylates and process for preparing them



United States Patent 3,461,145 A14-PREGNEN-3,21-DIOL-20-0NE-21 ACYLATES AND PROCESS FOR PREPARING THEM Werner Haede, Hofheirn, Taunus, Kurt Radscheit, Kelkheim, Taunus, Wemer Fritsch, Neuenhain, Taunus,

Patented Aug. 12, 1969 gesterone is at first converted by a biochemical method into 15a-hydroXy-progesterone; the aforesaid compound is then obtained after several chemical steps and a further biochemical process step in a yield of less than 1%.

Now, we have found that Al4-pregnene-3,2l-diol-20- Ulrich Stache, Hofheim, Taunus, and Heinrich Rus- 5 0ne-21-acylates of the 5a, 513- and A5 series can be chig, Bad Soden, Taunus, Germany, assignors to obtained by saponifying Al4,16-pre-gnadieneor A5,l4,16- P 9 Akfiellgesellschaft Y Melstel' pregnatriene-3-ol-20-one-acylates, converting the resulting Lucms Frankfurt am Mam! Germany a A14,16-pregnatriene-3-ol-20-ones into their tetrahydrol rzlw ir ig Fil e d F e 28 1967 Ser No 619 204 10 Pyranyl i dihydr9pyrane. tfyfimgenafing the Claims priority application fGennany M 1966, double bond n the 16,17-pos1tion, oxldizmg the hydroxy- 4 ,737 group WhlCh formed by simultaneous reduction of the Int, (31, C07: 169/36, 167/28 keto-group, separating the tetrahydropyranyl radical by US. Cl. 260--397.47 2 Claims hydrolysis and acyloxylating the compounds thus obtained 15 in the 21-position.

As starting materials, there is used the 5,14,l6-pregna- ABSTRACT OF THE DISCLOSURE triene-3fl-ol-ZO-one-acetate, which can easily be produced A14 pregnene 321 dio1 20 0ne 2Lacetates Such as A5 accordlng to Helv. Chim. Acta 30, 385 (1947) or accord- 14-pregnadiene-3B,21-diol-20-one-21 acetate and Al4-allomg to f 1658 (1965) or the acylates pregnene-3fl,21-diol-20-one-2l-acetate, useful as interof A14W'Pregnadlenes'ol'zo'ones Such as mediates in the synthesis of cardenolides. Method of z making these compounds from A14,16-pregnadieneor fi' or Sfl-Pregn? A5,14,16-pregnatriene-3-ol-20-one-acy1ates by hydrolysis, whlch can Produced etherification with dihydropyrane, reduction of the 16,17- analogous manner are double bond and of the 20-oxo group, reoxidation of the compounds may also carry other hydroxyl groups resultant hydroxy group to 20-oxo, hydrolysis of tetrathe mug Skeleton of rings B or as well as atthe hydropyranyl ethmgroups, and acetoxylation. methyl group at C 10. These hydroxyl groups must likewise be protected intermediarily as tetrahydropyranyl ether, in the same way as the 3-hydroxyl group. US. Patent 2,930,791 describes a process for preparing The reactions can P for p according to A14-pregnene-3a,21-dio1-20-one-2l-acetate, wherein prothe following scheme:

}=0 to I p-toluenesultonic acid H2O HBCCOO I HO II Dihydropyrane i0 nlon p (1 Na m ClOs 0 o 0 III 0 1v CH=C-COOC2H5 O ONa p \l/ H+ Oxalic ester In )0 H0 110.- CHaONa \0 V 1 VII CHzI OHaOCOOHa O O f KOCOCH VIII IX In most cases it is difiicult to obtain pure A14,16-dienes as starting material, because the hitherto known, above mentioned processes yield products which contain at best about 75% of A14,16-diene and 25% of A16-ene (starting material) (see Helv. 30, 390 (1947)). Purification by chromatography is possible, but very expensive and involves considerable losses.

The surprising finding that the Al4,16-pregnadiene-20- ones and the Al6-pregnene-20-ones show an important difference in their sensitivity to alkali is an advantage of the process of the present invention. Under the conditions of alkaline saponification and/or of a later treatment with alkali, the A16-pregnene compound is destroyed to a large extent whereas the A14,16-pregnadiene compound remains unaffected. The purity of the Al4,16-pregnadiene-3-ol-20- one is of importance in the process of the present invention. Because of the large number of reaction steps, the carrying along of one third of accompanying substance, which forms with the A14,l6-diene a mixed crystalline product, reduces the yield of the total synthesis to minimum amounts.

In contradistinction to the yields of the hitherto known process, the yield of the process of the present invention is times as high. In addition thereto, the process can be carried out in a simpler and more rapid manner, because a biochemical step is not necessary. In the known process, on the other hand, two biochemical steps are required.

It had to be expected that the A14,16-pregnadiene-20- ones would be sensitive to alkalies and that an attempt to saponify the 3-acyloxy group would result in an' undesirable by-reaction (addition to the double bond in 16,17-position).

The saponification can be carried out, in an alkaline medium, for example in diluted alkali, such as sodium hydroxide or potassium hydroxide solutions, alkali metal alcoholates or alkali metal carbonates or bicarbonates, but also in an aqueous solution of inert solvents which are miscible with water, for example, dioxane, tetrahydrofurane or acetone in the presence of sulfonic acids, for example, p-toluene-sulfonic acid, benzene-sulfonic acid or methane-sulfonic acid.

The introduction of the tetrahydropyranyl protecting group by means of dihydropyrane in the presence of an acid catalyst, such for example, as phosphorus oxy-chloride, hydrochloric acid, or p-toluene-sulfonic acid, is followed by the selective hydrogenation of the double bond in 16,17-position. It is advantageous to effect the reduction by means of Na or Li in propanol or liquid ammonia. Since the keto group is also reduced, it is necessary to regenerate it. This is most suitably done with CrO in pyridine. Hydrolysis of the tetrahydropyranyl ether IV is effected by means of acid catalysts such for example, as p-toluene-sulfonic acid or hydrochloric acid, by a short boiling up in an alcoholic solution or alcoholic-aqueous solution. The introduction of the acyloxy group into the 21-positi0n of the steroid molecule is suitably effected according to the method described in Chemische Berichte, volume 88, page 876 et seq. (1955).

The products of the present invention are valuable intermediate products for the preparation of cardenolides.

The following examples illustrate the invention, but they are not intended to limit it thereto:

EXAMPLE 1 84.5 grams of A5,14,l6-pregnadiene-3fl-ol-20-one-acerate (I) are dissolved in 1.2 liters of acetone. 85 grams of p-toluene-sulfonic acid in 320 cc. of water are added to the boiling solution. The reaction solution is heated for 8 hours to the boiling temperature. It is then neutralized with a sodium acetate solution and combined with 4 liters of Water. The precipitate is filtered off with suction, washed with water and then dried.

The crude product thus obtained is introduced into 400 cc. of tetrahydrofurane and combined while stirring and cooling and under an atmosphere of nitrogen with 48 cc. of dihydropyrane and 1 cc. of phosphorus oxychloride. After 1 hour at a temperature of 25 C., the reaction mixture is poured into 4 liters of a sodium bicarbonate solution having a strength of 0.5%. The precipitate which has formed is filtered off, washed with water and dried.

86.1 grams of the 3B-tetrahydropyranyl ether of A5,14, 16-pregnatriene-3,8-ol-20-one (II), melting at 165 169.5 C. are obtained.

These 86.1 grams are dissolved in 3.25 liters of n-propanol. 160 grams of sodium are added in the course of 5 hours to the boiling solution. The residue of sodium, which has not reacted, is dissolved by the addition of methanol and the reaction solution is poured into 12 liters of water. The precipitate, which has formed, is filtered off, washed with water and dried. 82.8 grams of the 3B-tetrahydropyranyl ether of A5,14-pregnadiene-3fl-20-diol (IV) melting at 125-127 are obtained.

This crude product is dissolved in 2 liters of pyridine. To this solution, there are slowly added, while stirring and cooling with ice and under nitrogen, 115 grams of CF03.

The reaction mixture is stirred over night at room temperature. Then, 115 cc. of isopropanol are slowly added and the whole is stirred for 20 minutes while cooling. The reaction mixture is diluted with 4 liters of methylene chloride and filtered through a layer of A1 0 (neutral, activity degree II). The filtrate is evaporated to dryness under reduced pressure and the residue is dissolved in ether and filtered through charcoal. After evaporation of the ether, 60 grams of the 3fl-tetrahydropyranyl ether of A5,l4-pregnadiene-3fl-ol-20-one (V) remain behind as crystalline residue. This crude product is dissolved in 1.2 liters of ethanol and boiled under reflux for 1% hours under nitrogen with 2 grams of p-toluene-sulfonic acid. After addition of 30 cc. of 2 N sodium acetate solution, the mixture is concentrated to 300 cc. and the product is precipitated by the addition of 1.5 liters of water. The precipitated product is filtered off, washed with water, dried and crystallized from ethyl acetate. Yield: 28.8 grams of A5,14-pregnadiene-3/3-ol-20-one (VI); melting point 205 -209 C.

Acetoxylation milligrams of sodium are dissolved in 2 cc. of methanol and, after addition of 10 cc. of benzene, the solution is concentrated to 4 cc. Then, 0.88 cc. of purified, freshly distilled diethyl oxalate are added at 5 C. The solution thus formed is then introduced into a hot solution of 1 gram of A5,14-pregnadiene-3{3-ol-20-one (VI) in 40 cc. of benzene. The temperature of the reaction mixture is maintained for 20 minutes at 70 C. During that time the sodium salt of the A5,14-pregnadiene-3fl-ol-20-one-21- oxalo ester (VII) separates, which, after cooling, is filtered off with suction and dried. This crude product (1.38 grams) is pulverized and suspended in 30 cc. of methanol. To this suspension, there is added dropwise, at 0 C., a solution of 1.2 grams of iodine in 20 cc. of methanol. When half of this iodine solution has been added, dropwise addition of 1.65 cc. of a 2 N sodium methylate solution is begun, care being taken that the addition of both solutions is completed at the same time. The whole is then stirred for 15 minutes at 20 C., and then combined with 300 cc. of water, while cooling.

The 2l-iodine-A5,14-pregnadiene-3/3-ol-20-one (VIII) which separates is filtered off with suction after some time, washed with water and dried in a desiccator over potassium hydroxide (1.5 grams of crude product). These 1.5 grams are boiled for 6 hours under reflux in a solution of 1.3 cc. of glacial acetic acid, 2.4 grams of potassium acetate and 30 cc. of water in cc. of acetone. After concentration of the solution and precipitation by the addition of water, 1.0 gram of A5,l4-pregnadiene-3[n- 21-diol-20-one-2l-acetate (IX) are obtained in form of a crude product. Melting point: l50-155 C. A purified sample, which has been recrystallized from diisopropyl ether, melts at 162164 C.

EXAMPLE 2 55 grams of a mixture as that obtained according to Helv. 30, 385 (1947), containing 72% of 14,16-allopregnadiene-3fl-ol-ZO-one-acetate (e :8,600) is boiled under reflux, for 5 hours, with 45 grams of sodium bicarbonate and 450 0c. of water. The solution is then concentrated until crystallization takes place. After neutralization with concentrated hydrochloric acid, 750 cc. of water are added. After cooling, the product is filtered off with suction and dried. The crude product is crystallized from methanol and then again heated for 1 hour under reflux in 1 liter of methanol with grams of sodium bicarbonate and 300 cc. of water. After concentration, neutralization and filtration with suction, the product is crystallized from methanol. grams of l4,16-allopregnadiene-3B-ol-20-one, having a purity of 90% (e =l0,800) and melting at 162-166 C., are obtained.

This product is introduced into 120 cc. of tetrahydrofurane with cc. of dihydropyrane and 0.3 cc. of phosphorus oxychloride and the whole is stirred for 24 hours at room temperature. After precipitation by means of Water containing sodium bicarbonate, the tetrahydropyranyl ether is obtained in form of a crude product. After crystallization from methanol, grams of the product melting at 140-l50 C., are obtained.

The crude product, obtained after reduction carried out in a manner analogous to that described in Example 1 in 1600 cc. of n-propanol with 80 grams of sodium, is dissolved in 880 cc. of pyridine and oxidized and hydrolized with 64 grams of CrO in a manner analogous to that described in Example 1. After recrystallization from ethyl acetate, 18 grams of A14-allopregnene-3fl-ol-20-one, melting at 181183 C., are obtained.

Acetoxylation 405 milligrams of sodium are dissolved in 10 cc. of methanol, and after addition of cc. of benzene, the solution is concentrated to 25 cc. 4.5 cc. of purified, freshly distilled di-ethyl oxalate are added at 5 C. The solution thus formed is introduced into a hot solution of 5 grams of A14-allopregnene-3B-ol-20-one in 150 cc. of benzene. The reaction mixture is kept for 20 minutes at a temperature of C. The sodium salt of the A14-al1opregnene-B'fi-ol-ZO-one-Zl-oxalo ester which has separated is filtered off with suction, washed with benzene and dried (6.9 grams). This crude product is pulverized, suspended in cc. of methanol and combined at -10 C., in the course of 30 minutes with a solution of 4.03 grams of iodine in 75 cc. of methanol. After 30 minutes, a solution of sodium methylate (365 mg. of sodium in 20 cc. of methanol) is added dropwise. The 2l-iodine-A14- allopregnene-3[3-ol-20-one which is formed, is precipita'ted after another 30 minutes by means of 300 cc. of water. In order to improve the separation, 300 cc. of a concentrated sodium chloride solution are added.

The crude still wet product in 350 cc. of acetone is combined with a solution of 6.5 cc. of glacial acetic acid and 12 grams of potassium acetate in cc. of water and boiled for 5 hours under reflux. After concentration of the solution and addition of water, a precipitate is obtained which is filtrated off with suction and dried. This crude product is extracted with ether and the ether solution is concentrated. 2.7 grams of Al4-allopregnene- 3 s, 21-di0l-20-one-2l-acetate, melting at l60-l64 C., are obtained. Another 0.6 gram can be recovered from the mother liquor.

We claim:

1. A5,14-pregnadiene-3;8,21-diol-20-one-2l-acetate.

2. A process for the manufacture of A14-pregnene-3, 2l-diol-20-one-2l-acetates of the Saw, 5B-, and AS-series which comprises hydrolyzing a Al4-l6-pregnadiene-3-ol- 20-one-acylate or a A5,14,l6-pregnatriene-3-ol-20-oneacylate; etherifying the hydroxy group of the resultant compound with dihydropyrane to form a tetrahydropyranyl ether; reducing the l6,l7-double bond with an alkali metal, whereby the keto group is also reduced to form an hydroxy group; reoxidizing this hydroxy group to a keto group with chromium trioxide; removing the tetrahydropyranyl ether group by hydrolysis; and acetoxylating the compound in the 21-position by forming its 21-oxalo-ester, reacting the ester with iodine to form the correpsonding 21-iodo compound, and reacting the latter with an acetate to form the desired 21-acetate.

References Cited UNITED STATES PATENTS 2,930,791 3/1960 Meister et .al. 260-23957 ELBERT L. ROBERTS, Primary Examiner U.S. c1. X.R, -51; 260239, 397, 999 

